Bacterial biofilm control by perturbation of bacterial signaling processes

International Journal of Molecular Sciences

Volumn 18, Issue 9, 2017, Pages

  Jakobsen, Tim Holm ^a   Tolker Nielsen, Tim ^a   Givskov, Michael ^a,b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b NANYANG TECHNOLOGICAL UNIVERSITY   (Singapore)

Author keywords

Anti virulence; Biofilm life cycle; Cell signaling; Cyclic di GMP; Pseudomonas aeruginosa; Quorum sensing; Small RNAs

Indexed keywords

ADHESIN; ALGINIC ACID; ANTIINFECTIVE AGENT; AZITHROMYCIN; BACTERIAL POLYSACCHARIDE; BACTERIAL PROTEIN; BIS (3' 5') DIMERIC GUANOSINE MONOPHOSPHATE; ERUCIN; EXOENZYME; EXOPOLYSACCHARIDE; FURANONE DERIVATIVE; GARLIC EXTRACT; IBERIN; N ACYLHOMOSERINE LACTONE; PATULIN; PENICILLIC ACID; PHENAZINE DERIVATIVE; PLANT EXTRACT; PYOCHELIN; PYOCYANINE; PYOVERDINE; QUORUM SENSING INHIBITOR; RHAMNOLIPID; RSMA PROTEIN; RSMY; RSMZ; SIDEROPHORE; SMALL UNTRANSLATED RNA; SURFACE ADHESIN CDRA; UNCLASSIFIED DRUG; UNINDEXED DRUG; BIS(3',5')-CYCLIC DIGUANYLIC ACID; CYCLIC GMP;

ANTIMICROBIAL ACTIVITY; BACTERIAL GENE; BACTERIUM PILUS; BIOFILM; CELL COMMUNICATION; DRUG SCREENING; EXTRACELLULAR FLUID; EXTRACELLULAR MATRIX; GAC/RSM CASCADE; GENE EXPRESSION REGULATION; GENETIC TRANSDUCTION; HUMAN; INTRACELLULAR SIGNALING; IRON TRANSPORT; NONHUMAN; POPULATION DISPERSION; PSEUDOMONAS AERUGINOSA; QUORUM SENSING; QUORUM SENSING INHIBITION; REGULATORY MECHANISM; REVIEW; SECOND MESSENGER; SIGNAL TRANSDUCTION; ANALOGS AND DERIVATIVES; BACTERIAL PHENOMENA AND FUNCTIONS; BACTERIUM; DRUG EFFECT; GROWTH, DEVELOPMENT AND AGING; METABOLISM; PHYSIOLOGY;

BACTERIA; BACTERIAL PHYSIOLOGICAL PHENOMENA; BIOFILMS; CYCLIC GMP; HUMANS; QUORUM SENSING; SIGNAL TRANSDUCTION;

EID: 85029677111     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms18091970     Document Type: Review

References (191)

1. Potera, C. Studying slime. Environ. Health Perspect. 1998, 106, A604-A606
2. Costerton, J.W.; Lewandowski, Z. Microbial biofilms. Annu. Rev. Microbiol. 1995, 49, 711-745
3. Høiby, N.; Bjarnsholt, T.; Givskov, M.; Molin, S.; Ciofu, O. Antibiotic resistance of bacterial biofilms. Int. J. Antimicrob. Agents 2010, 35, 322-332
4. Bjarnsholt, T.; Givskov, M. The role of quorum sensing in the pathogenicity of the cunning aggressor Pseudomonas aeruginosa. Anal. Bioanal. Chem. 2007, 387, 409-414
5. Costerton, J.W.; Stewart, P.S.; Greenberg, E.P. Bacterial biofilms: A common cause of persistent infections. Science 1999, 284, 1318-1322
6. Post, J.C. Direct evidence of bacterial biofilms in otitis media. Laryngoscope 2001, 111, 2083-2094
7. Barbosa, F.C.; Mayer, M.P.; Saba-Chujfi, E.; Cai, S. Subgingival occurrence and antimicrobial susceptibility of enteric rods and pseudomonads from Brazilian periodontitis patients. Oral Microbiol. Immunol. 2001, 16, 306-310
8. Lyczak, J.B.; Cannon, C.L.; Pier, G.B. Establishment of Pseudomonas aeruginosa infection: Lessons from a versatile opportunist. Microbes Infect. 2000, 2, 1051-1060
9. Obritsch, M.D.; Fish, D.N.; MacLaren, R.; Jung, R. Nosocomial infections due to multidrug-resistant Pseudomonas aeruginosa: Epidemiology and treatment options. Pharmacotherapy 2005, 25, 1353-1364
10. Woodward, T.C.; Brown, R.; Sacco, P.; Zhang, J. Budget impact model of tobramycin inhalation solution for treatment of Pseudomonas aeruginosa in cystic fibrosis patients. J. Med. Econ. 2010, 13, 492-499
11. Koch, C.; Hoiby, N. Pathogenesis of cystic fibrosis. Lancet 1993, 341, 1065-1069
12. Hentzer, M.; Wu, H.; Andersen, J.B.; Riedel, K.; Rasmussen, T.B.; Bagge, N.; Kumar, N.; Schembri, M.A.; Song, Z.; Kristoffersen, P.; et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J. 2003, 22, 3803-3815
13. Hentzer, M.; Riedel, K.; Rasmussen, T.B.; Heydorn, A.; Andersen, J.B.; Parsek, M.R.; Rice, S.A.; Eberl, L.; Molin, S.; Høiby, N.; et al. Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology 2002, 148, 87-102
14. Hentzer, M.; Givskov, M. Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections. J. Clin. Investig. 2003, 112, 1300-1307
15. Zuker, M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 2003, 31, 3406-3415
16. Gómez, M.I.; Prince, A. Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis. Curr. Opin. Pharmacol. 2007, 7, 244-251
17. Stoodley, P.; Sauer, K.; Davies, D.G.; Costerton, J.W. Biofilms as complex differentiated communities. Annu. Rev. Microbiol. 2002, 56, 187-209
18. O’Toole, G.; Kaplan, H.B.; Kolter, R. Biofilm formation as microbial development. Annu. Rev. Microbiol. 2000, 54, 49-79
19. Sauer, K. The genomics and proteomics of biofilm formation. Genome Biol. 2003, 4, 219
20. Purevdorj, B.; Costerton, J.W.; Stoodley, P. Influence of hydrodynamics and cell signaling on the structure and behavior of Pseudomonas aeruginosa biofilms. Appl. Environ. Microbiol. 2002, 68, 4457-4464
21. Reimmann, C.; Ginet, N.; Michel, L.; Keel, C.; Michaux, P.; Krishnapillai, V.; Zala, M.; Heurlier, K.; Triandafillu, K.; Harms, H.; et al. Genetically programmed autoinducer destruction reduces virulence gene expression and swarming motility in Pseudomonas aeruginosa PAO1. Microbiology 2002, 148, 923-932
22. Hentzer, M.; Eberl, L.; Givskov, M. Transcriptome analysis of Pseudomonas aeruginosa biofilm development: Anaerobic respiration and iron limitation. Biofilms 2005, 2, 37-61
23. Flemming, H.; Wingender, J. The biofilm matrix. Nat. Rev. Microbiol. 2010, 8, 623-633
24. Allesen-Holm, M.; Barken, K.B.; Yang, L.; Klausen, M.; Webb, J.S.; Kjelleberg, S.; Molin, S.; Givskov, M.; Tolker-Nielsen, T. A characterization of DNA release in Pseudomonas aeruginosa cultures and biofilms. Mol. Microbiol. 2006, 59, 1114-1128
25. Whitchurch, C.B.; Tolker-Nielsen, T.; Ragas, P.C.; Mattick, J.S. Extracellular DNA Required for bacterial biofilm formation. Science 2002, 295, 1487
26. Barken, K.B.; Pamp, S.J.; Yang, L.; Gjermansen, M.; Bertrand, J.J.; Klausen, M.; Givskov, M.; Whitchurch, C.B.; Engel, J.N.; Tolker-Nielsen, T. Roles of type IV pili, flagellum-mediated motility and extracellular DNA in the formation of mature multicellular structures in Pseudomonas aeruginosa biofilms. Environ. Microbiol. 2008, 10, 2331-2343
27. Yang, L.; Barken, K.B.; Skindersoe, M.E.; Christensen, A.B.; Givskov, M.; Tolker-Nielsen, T. Effects of iron on DNA release and biofilm development by Pseudomonas aeruginosa. Microbiology 2007, 153, 1318-1328
28. Thomson, A.H. Human recombinant DNase in cystic fibrosis. J. R. Soc. Med. 1995, 88, 24-29
29. Ranasinha, C.; Assoufi, B.; Geddes, D.; Hodson, M.; Empey, D.; Shak, S.; Christiansen, D.; Fuchs, H. Efficacy and safety of short-term administration of aerosolised recombinant human DNase I in adults with stable stage cystic fibrosis. Lancet 1993, 342, 199-202
30. Ramsey, B.W.; Astley, S.J.; Aitken, M.L.; Burke, W.; Colin, A.A.; Dorkin, H.L.; Eisenberg, J.D.; Gibson, R.L.; Harwood, I.R.; Schidlow, D.V.; et al. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am. Rev. Respir. Dis. 1993, 148, 145-151
31. Fuchs, H.J.; Borowitz, D.S.; Christiansen, D.H.; Morris, E.M.; Nash, M.L.; Ramsey, B.W.; Rosenstein, B.J.; Smith, A.L.; Wohl, M.E. Effect of Aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N. Engl. J. Med. 1994, 331, 637-642
32. Mathee, K.; Ciofu, O.; Sternberg, C.; Lindum, P.W.; Campbell, J.I.A.; Jensen, P.; Johnsen, A.H.; Givskov, M.; Ohman, D.E.; Molin, S.; et al. Mucoid conversion of Pseudomonas aeruginosa by hydrogen peroxide: A mechanism for virulence activation in the cystic fibrosis lung. Microbiology 1999, 145, 1349-1357
33. Friedman, L.; Kolter, R. Two genetic loci produce distinct carbohydrate-rich structural components of the Pseudomonas aeruginosa biofilm matrix. J. Bacteriol. 2004, 186, 4457-4465
34. Vasseur, P.; Vallet-Gely, I.; Soscia, C.; Genin, S.; Filloux, A. The pel genes of the Pseudomonas aeruginosa PAK strain are involved at early and late stages of biofilm formation. Microbiology 2005, 151, 985-997
35. Colvin, K.M.; Gordon, V.D.; Murakami, K.; Borlee, B.R.; Wozniak, D.J.; Wong, G.C.L.; Parsek, M.R. The pel polysaccharide can serve a structural and protective role in the biofilm matrix of Pseudomonas aeruginosa. PLoS Pathog.2011, 7, e1001264
36. Coulon, C.; Vinogradov, E.; Filloux, A.; Sadovskaya, I. Chemical analysis of cellular and extracellular carbohydrates of a biofilm-forming strain Pseudomonas aeruginosa PA14. PLoS ONE 2010, 5, e14220
37. Byrd, M.S.; Sadovskaya, I.; Vinogradov, E.; Lu, H.; Sprinkle, A.B.; Richardson, S.H.; Ma, L.; Ralston, B.; Parsek, M.R.; Anderson, E.M.; et al. Genetic and biochemical analyses of the Pseudomonas aeruginosa Psl exopolysaccharide reveal overlapping roles for polysaccharide synthesis enzymes in Psl and LPS production. Mol. Microbiol. 2009, 73, 622-638
38. Colvin, K.M.; Irie, Y.; Tart, C.S.; Urbano, R.; Whitney, J.C.; Ryder, C.; Howell, P.L.; Wozniak, D.J.; Parsek, M.R. The Pel and Psl polysaccharides provide Pseudomonas aeruginosa structural redundancy within the biofilm matrix. Environ. Microbiol. 2012, 14, 1913-1928
39. Schleheck, D.; Barraud, N.; Klebensberger, J.; Webb, J.S.; McDougald, D.; Rice, S.A.; Kjelleberg, S. Pseudomonas aeruginosa PAO1 preferentially grows as aggregates in liquid batch cultures and disperses upon starvation. PLoS ONE2009, 4, e5513
40. Sauer, K.; Cullen, M.C.; Rickard, A.H.; Zeef, L.A.H.; Davies, D.G.; Gilbert, P. Characterization of nutrient-induced dispersion in Pseudomonas aeruginosa PAO1 biofilm. J. Bacteriol. 2004, 186, 7312-7326
41. Barraud, N.; Hassett, D.J.; Hwang, S.H.; Rice, S.A.; Kjelleberg, S.; Webb, J.S. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J. Bacteriol. 2006, 188, 7344-7353
42. Banin, E.; Brady, K.M.; Greenberg, E.P. Chelator-induced dispersal and killing of Pseudomonas aeruginosa cells in a biofilm. Appl. Environ. Microbiol. 2006, 72, 2064-2069
43. Romling, U.; Galperin, M.Y.; Gomelsky, M. Cyclic di-GMP: The first 25 years of a universal bacterial second messenger. Microbiol. Mol. Biol. Rev. 2013, 77, 1-52
44. Schuster, M.; Lostroh, C.P.; Ogi, T.; Greenberg, E.P. Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: A transcriptome analysis. J. Bacteriol. 2003, 185, 2066-2079
45. Wagner, V.E.; Bushnell, D.; Passador, L.; Brooks, A.I.; Iglewski, B.H. Microarray analysis of Pseudomonas aeruginosaquorum-sensing regulons: Effects of growth phase and environment. J. Bacteriol. 2003, 185, 2080-2095
46. Howe, T.R.; Iglewski, B.H. Isolation and characterization of alkaline protease-deficient mutants of Pseudomonas aeruginosain vitro and in a mouse eye model. Infect. Immun. 1984, 43, 1058-1063
47. Woods, D.E.; Cryz, S.J.; Friedman, R.L.; Iglewski, B.H. Contribution of toxin A and elastase to virulence of Pseudomonas aeruginosa in chronic lung infections of rats. Infect. Immun. 1982, 36, 1223-1228
48. Vasil, M.L.; Grant, C.C.R.; Prince, R.W. Regulation of exotoxin A synthesis in Pseudomonas aeruginosa: Characterization of toxA-lacZ fusions in wild-type and mutant strains. Mol. Microbiol. 1989, 3, 371-381
49. Nicas, T.I.; Frank, D.W.; Stenzel, P.; Lile, J.D.; Iglewski, B.H. Role of exoenzyme S in chronic Pseudomonas aeruginosalung infections. Eur. J. Clin. Microbiol. 1985, 4, 175-179
50. Cox, C.D. Effect of pyochelin on the virulence of Pseudomonas aeruginosa. Infect. Immun. 1982, 36, 17-23
51. Ochsner, U.A.; Reiser, J. Autoinducer-mediated regulation of rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 1995, 92, 6424-6428
52. Bjarnsholt, T.; Jensen, P.Ø.; Burmølle, M.; Hentzer, M.; Haagensen, J.A.J.; Hougen, H.P.; Calum, H.; Madsen, K.G.; Moser, C.; Molin, S.; et al. Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent. Microbiology 2005, 151, 373-383
53. Yang, L.; Nilsson, M.; Gjermansen, M.; Givskov, M.; Tolker-Nielsen, T. Pyoverdine and PQS mediated subpopulation interactions involved in Pseudomonas aeruginosa biofilm formation. Mol. Microbiol. 2009, 74, 1380-1392
54. Shak, S.; Capon, D.J.; Hellmiss, R.; Marsters, S.A.; Baker, C.L. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc. Natl. Acad. Sci. USA 1990, 87, 9188-9192
55. Ramphal, R.; Lhermitte, M.; Filliat, M.; Roussel, P. The binding of anti-pseudomonal antibiotics to macromolecules from cystic fibrosis sputum. J. Antimicrob. Chemother. 1988, 22, 483-490
56. Hunt, B.E.; Weber, A.; Berger, A.; Ramsey, B.; Smith, A.L. Macromolecular mechanisms of sputum inhibition of tobramycin activity. Antimicrob. Agents Chemother. 1995, 39, 34-39
57. Drew, K.R.P.; Sanders, L.K.; Culumber, Z.W.; Zribi, O.; Wong, G.C.L. Cationic amphiphiles increase activity of aminoglycoside antibiotic tobramycin in the presence of airway polyelectrolytes. J. Am. Chem. Soc. 2009, 131, 486-493
58. Mulcahy, H.; Charron-Mazenod, L.; Lewenza, S. Extracellular DNA chelates cations and induces antibiotic resistance in Pseudomonas aeruginosa biofilms. PLoS Pathog. 2008, 4, e1000213
59. Walker, T.S.; Tomlin, K.L.; Worthen, G.S.; Poch, K.R.; Lieber, J.G.; Saavedra, M.T.; Fessler, M.B.; Malcolm, K.C.; Vasil, M.L.; Nick, J.A. Enhanced Pseudomonas aeruginosa biofilm development mediated by human neutrophils. Infect. Immun.2005, 73, 3693-3701
60. Chiang, W.C.; Nilsson, M.; Jensen, P.Ø.; Høiby, N.; Nielsen, T.E.; Givskov, M.; Tolker-Nielsen, T. Extracellular DNA shields against aminoglycosides in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 2013, 57, 2352-2361
61. Mahajan-Miklos, S.; Tan, M.W.; Rahme, L.G.; Ausubel, F.M. Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model. Cell 1999, 96, 47-56
62. Wilson, R.; Sykes, D.A.; Watson, D.; Rutman, A.; Taylor, G.W.; Cole, P.J. Measurement of Pseudomonas aeruginosaphenazine pigments in sputum and assessment of their contribution to sputum sol toxicity for respiratory epithelium. Infect. Immun. 1988, 56, 2515-2517
63. Nutman, J.; Chase, P.A.; Dearborn, D.G.; Berger, M.; Sorensen, R.U. Suppression of lymphocyte proliferation by Pseudomonas aeruginosa phenazine pigments. ISR J. Med. Sci. 1988, 24, 228-232
64. Britigan, B.E.; Railsback, M.A.; Cox, C.D. The Pseudomonas aeruginosa secretory product pyocyanin inactivates alpha1 protease inhibitor: Implications for the pathogenesis of cystic fibrosis lung disease. Infect. Immun. 1999, 67, 1207-1212
65. Denning, G.M.; Railsback, M.A.; Rasmussen, G.T.; Cox, C.D.; Britigan, B.E. Pseudomonas pyocyanine alters calcium signaling in human airway epithelial cells. Am. J. Physiol. 1998, 274, L893-L900
66. Kamath, J.M.; Britigan, B.E.; Cox, C.D.; Shasby, D.M. Pyocyanin from Pseudomonas aeruginosa inhibits prostacyclin release from endothelial cells. Infect. Immun. 1995, 63, 4921-4923
67. Mühlradt, P.F.; Tsai, H.; Conradt, P. Effects of pyocyanine, a blue pigment from Pseudomonas aeruginosa, on separate steps of T cell activation: Interleukin 2 (IL 2) production, IL 2 receptor formation, proliferation and induction of cytolytic activity. Eur. J. Immunol. 1986, 16, 434-440
68. Das, T.; Manefield, M. Pyocyanin promotes extracellular DNA release in Pseudomonas aeruginosa. PLoS ONE 2012, 7, e46718
69. Das, T.; Kutty, S.K.; Tavallaie, R.; Ibugo, A.I.; Panchompoo, J.; Sehar, S.; Aldous, L.; Yeung, A.W.S.; Thomas, S.R.; Kumar, N.; et al. Phenazine virulence factor binding to extracellular DNA is important for Pseudomonas aeruginosabiofilm. Sci. Rep. 2015, 5, 1-9
70. Maier, R.M.; Soberón-Chávez, G. Pseudomonas aeruginosa rhamnolipids: Biosynthesis and potential applications. Appl. Microbiol. Biotechnol. 2000, 54, 625-633
71. Rendell, N.B.; Taylor, G.W.; Somerville, M.; Todd, H.; Wilson, R.; Cole, P.J. Characterisation of Pseudomonas rhamnolipids. Biochim. Biophys. Acta (BBA) Lipids Lipid Metab. 1990, 1045, 189-193
72. Ochsner, U.A.; Koch, A.K.; Fiechter, A.; Reiser, J. Isolation and characterization of a regulatory gene affecting rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. J. Bacteriol. 1994, 176, 2044-2054
73. Rahim, R.; Ochsner, U.A.; Olvera, C.; Graninger, M.; Messner, P.; Lam, J.S.; Soberón-Chávez, G. Cloning and functional characterization of the Pseudomonas aeruginosa rhlC gene that encodes rhamnosyltransferase 2, an enzyme responsible for di-rhamnolipid biosynthesis. Mol. Microbiol. 2001, 40, 708-718
74. Johnson, M.K.; Boese-Marrazzo, D. Production and properties of heat-stable extracellular hemolysin from Pseudomonas aeruginosa. Infect. Immun. 1980, 29, 1028-1033
75. Jensen, P.; Bjarnsholt, T.; Phipps, R.; Rasmussen, T.B.; Calum, H.; Christoffersen, L.; Moser, C.; Williams, P.; Pressler, T.; Givskov, M.; et al. Rapid necrotic killing of polymorphonuclear leukocytes is caused by quorum-sensing-controlled production of rhamnolipid by Pseudomonas aeruginosa. Microbiology 2007, 153, 1329-1338
76. McClure, C.D.; Schiller, N.L. Effects of Pseudomonas aeruginosa rhamnolipids on human monocyte-derived macrophages. J. Leukoc. Biol. 1992, 51, 97-102
77. Shryock, T.R.; Silver, S.A.; Banschbach, M.W.; Kramer, J.C. Effect of Pseudomonas aeruginosa rhamnolipid on human neutrophil migration. Curr. Microbiol. 1984, 10, 323-328
78. Déziel, E.; Lépine, F.; Milot, S.; Villemur, R. rhlA is required for the production of a novel biosurfactant promoting swarming motility in Pseudomonas aeruginosa: 3-(3-Hydroxyalkanoyloxy)alkanoic acids (HAAs), the precursors of rhamnolipids. Microbiology 2003, 149, 2005-2013
79. Davey, M.E.; Caiazza, N.C.; O’Toole, G.A. Rhamnolipid surfactant production affects biofilm architecture in Pseudomonas aeruginosa PAO1. J. Bacteriol. 2003, 185, 1027-1036
80. Haba, E.; Pinazo, A.; Jauregui, O.; Espuny, M.J.; Infante, M.R.; Manresa, A. Physicochemical characterization and antimicrobial properties of rhamnolipids produced by Pseudomonas aeruginosa 47T2 NCBIM 40044. Biotechnol. Bioeng.2003, 81, 316-322
81. Soberón-Chávez, G.; Aguirre-Ramírez, M.; Sánchez, R. The Pseudomonas aeruginosa RhlA enzyme is involved in rhamnolipid and polyhydroxyalkanoate production. J. Ind. Microbiol. Biotechnol. 2005, 32, 675
82. Read, R.C.; Roberts, P.; Munro, N.; Rutman, A.; Hastie, A.; Shryock, T.; Hall, R.; McDonald-Gibson, W.; Lund, V.; Taylor, G. Effect of Pseudomonas aeruginosa rhamnolipids on mucociliary transport and ciliary beating. J. Appl. Physiol.1992, 72, 2271-2277
83. Zulianello, L.; Canard, C.; Köhler, T.; Caille, D.; Lacroix, J.S.; Meda, P. Rhamnolipids are virulence factors that promote early infiltration of primary human airway epithelia by Pseudomonas aeruginosa. Infect. Immun. 2006, 74, 3134-3147
84. Bjarnsholt, T.; Givskov, M. Quorum sensing inhibitory drugs as next generation antimicrobials: Worth the effort? Curr. Infect. Dis. Rep. 2008, 10, 22-28
85. Alhede, M.; Bjarnsholt, T.; Jensen, P.; Phipps, R.K.; Moser, C.; Christophersen, L.; Christensen, L.D.; van Gennip, M.; Parsek, M.; Høiby, N.; et al. Pseudomonas aeruginosa recognizes and responds aggressively to the presence of polymorphonuclear leukocytes. Microbiology 2009, 155, 3500-3508
86. Morici, L.A.; Carterson, A.J.; Wagner, V.E.; Frisk, A.; Schurr, J.R.; Zu Bentrup, K.H.; Hassett, D.J.; Iglewski, B.H.; Sauer, K.; Schurr, M.J. Pseudomonas aeruginosa AlgR represses the Rhl quorum-sensing system in a biofilm-specific manner. J. Bacteriol. 2007, 189, 7752-7764
87. Van Gennip, M.; Christensen, L.D.; Alhede, M.; Phipps, R.; Jensen, P.Ø.; Christophersen, L.; Pamp, S.J.; Moser, C.; Mikkelsen, P.J.; Koh, A.Y.; et al. Inactivation of the rhlA gene in Pseudomonas aeruginosa prevents rhamnolipid production, disabling the protection against polymorphonuclear leukocytes. APMIS 2009, 117, 537-546
88. Lee, J.; Wu, J.; Deng, Y.; Wang, J.; Wang, C.; Wang, J.; Chang, C.; Dong, Y.; Williams, P.; Zhang, L.-H. A cell-cell communication signal integrates quorum sensing and stress response. Nat. Chem. Biol. 2013, 9, 339-343
89. Ciofu, O.; Mandsberg, L.F.; Bjarnsholt, T.; Wassermann, T.; Høiby, N. Genetic adaptation of Pseudomonas aeruginosaduring chronic lung infection of patients with cystic fibrosis: Strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants. Microbiology 2010, 156, 1108-1119
90. Hoffman, L.R.; Kulasekara, H.D.; Emerson, J.; Houston, L.S.; Burns, J.L.; Ramsey, B.W.; Miller, S.I. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J. Cyst. Fibros. 2009, 8, 66-70
91. Smith, E.E.; Buckley, D.G.; Wu, Z.; Saenphimmachak, C.; Hoffman, L.R.; D’Argenio, D.A.; Miller, S.I.; Ramsey, B.W.; Speert, D.P.; Moskowitz, S.M.; et al. V Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc. Natl. Acad. Sci. USA 2006, 103, 8487-8492
92. D’Argenio, D.A.; Wu, M.; Hoffman, L.R.; Kulasekara, H.D.; Déziel, E.; Smith, E.E.; Nguyen, H.; Ernst, R.K.; Larson Freeman, T.J.; Spencer, D.H.; et al. Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients. Mol. Microbiol. 2007, 64, 512-533
93. Bjarnsholt, T.; Jensen, P.Ø.; Jakobsen, T.H.; Phipps, R.; Nielsen, A.K.; Rybtke, M.T.; Tolker-Nielsen, T.; Givskov, M.; Høiby, N.; Ciofu, O. Quorum sensing and virulence of Pseudomonas aeruginosa during lung infection of cystic fibrosis patients. PLoS ONE 2010, 5, e10115
94. Römling, U.; Amikam, D. Cyclic di-GMP as a second messenger. Curr. Opin. Microbiol. 2006, 9, 218-228
95. Galperin, M.Y. Bacterial signal transduction network in a genomic perspective. Environ. Microbiol. 2004, 6, 552-567
96. Hengge, R. Principles of c-di-GMP signalling in bacteria. Nat. Rev. Microbiol. 2009, 7, 263-273
97. Christen, M.; Christen, B.; Folcher, M.; Schauerte, A.; Jenal, U. Identification and characterization of a cyclic di-GMP-specific phosphodiesterase and its allosteric control by GTP. J. Biol. Chem. 2005, 280, 30829-30837
98. Ryan, R.P.; Fouhy, Y.; Lucey, J.F.; Crossman, L.C.; Spiro, S.; He, Y.-W.; Zhang, L.-H.; Heeb, S.; Cámara, M.; Williams, P.; et al. Cell-cell signaling in Xanthomonas campestris involves an HD-GYP domain protein that functions in cyclic di-GMP turnover. Proc. Natl. Acad. Sci. USA 2006, 103, 6712-6717
99. Kulasakara, H.; Lee, V.; Brencic, A.; Liberati, N.; Urbach, J.; Miyata, S.; Lee, D.G.; Neely, A.N.; Hyodo, M.; Hayakawa, Y.; et al. Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3’-5’)-cyclic-GMP in virulence. Proc. Natl. Acad. Sci. USA 2006, 103, 2839-2844
100. Düvel, J.; Bertinetti, D.; Möller, S.; Schwede, F.; Morr, M.; Wissing, J.; Radamm, L.; Zimmermann, B.; Genieser, H.G.; Jänsch, L.; et al. A chemical proteomics approach to identify c-di-GMP binding proteins in Pseudomonas aeruginosa. J. Microbiol. Methods 2012, 88, 229-236
101. Hay, I.D.; Remminghorst, U.; Rehm, B.H.A. MucR, a novel membrane-associated regulator of alginate biosynthesis in Pseudomonas aeruginosa. Appl. Environ. Microbiol. 2009, 75, 1110-1120
102. Hickman, J.W.; Harwood, C.S. Identification of FleQ from Pseudomonas aeruginosa as a c-di-GMP-responsive transcription factor. Mol. Microbiol. 2008, 69, 376-389
103. Lee, V.T.; Matewish, J.M.; Kessler, J.L.; Hyodo, M.; Hayakawa, Y.; Lory, S. A cyclic-di-GMP receptor required for bacterial exopolysaccharide production. Mol. Microbiol. 2007, 65, 1474-1484
104. Meissner, A.; Wild, V.; Simm, R.; Rohde, M.; Erck, C.; Bredenbruch, F.; Morr, M.; Römling, U.; Häussler, S. Pseudomonas aeruginosa cupA-encoded fimbriae expression is regulated by a GGDEF and EAL domain-dependent modulation of the intracellular level of cyclic diguanylate. Environ. Microbiol. 2007, 9, 2475-2485
105. Borlee, B.R.; Goldman, A.D.; Murakami, K.; Samudrala, R.; Wozniak, D.J.; Parsek, M.R. Pseudomonas aeruginosa uses a cyclic-di-GMP-regulated adhesin to reinforce the biofilm extracellular matrix. Mol. Microbiol. 2010, 75, 827-842
106. Christensen, L.D.; van Gennip, M.; Rybtke, M.T.; Wu, H.; Chiang, W.C.; Alhede, M.; Høiby, N.; Nielsen, T.E.; Givskov, M.; Tolker-Nielsena, T. Clearance of Pseudomonas aeruginosa foreign-body biofilm infections through reduction of the cyclic di-gmp level in the bacteria. Infect. Immun. 2013, 81, 2705-2713
107. Huang, B.; Whitchurch, C.B.; Mattick, J.S. FimX, a multidomain protein connecting environmental signals to twitching motility in Pseudomonas aeruginosa. J. Bacteriol. 2003, 185, 7068-7076
108. Guzzo, C.R.; Salinas, R.K.; Andrade, M.O.; Farah, C.S. PILZ Protein Structure and Interactions with PILB and the FIMX EAL Domain: Implications for Control of Type IV Pilus Biogenesis. J. Mol. Biol. 2009, 393, 848-866
109. Kulasekara, H.D.; Ventre, I.; Kulasekara, B.R.; Lazdunski, A.; Filloux, A.; Lory, S. A novel two-component system controls the expression of Pseudomonas aeruginosa fimbrial cup genes. Mol. Microbiol. 2005, 55, 368-380
110. Mikkelsen, H.; Ball, G.; Giraud, C.; Filloux, A. Expression of Pseudomonas aeruginosa CupD Fimbrial genes is antagonistically controlled by RcsB and the EAL-containing PvrR response regulators. PLoS ONE 2009, 4, e6018
111. Rao, F.; Yang, Y.; Qi, Y.; Liang, Z.-X. Catalytic mechanism of cyclic di-GMP-specific phosphodiesterase: A study of the EAL domain-containing RocR from Pseudomonas aeruginosa. J. Bacteriol. 2008, 190, 3622-3631
112. D’Argenio, D.A.; Calfee, M.W.; Rainey, P.B.; Pesci, E.C. Autolysis and autoaggregation in Pseudomonas aeruginosa colony morphology mutants. J. Bacteriol. 2002, 184, 6481-6489
113. Klebensberger, J.; Lautenschlager, K.; Bressler, D.; Wingender, J.; Philipp, B. Detergent-induced cell aggregation in subpopulations of Pseudomonas aeruginosa as a preadaptive survival strategy. Environ. Microbiol. 2007, 9, 2247-2259
114. Klebensberger, J.; Birkenmaier, A.; Geffers, R.; Kjelleberg, S.; Philipp, B. SiaA and SiaD are essential for inducing autoaggregation as a specific response to detergent stress in Pseudomonas aeruginosa. Environ. Microbiol. 2009, 11, 3073-3086
115. Irie, Y.; Starkey, M.; Edwards, A.N.; Wozniak, D.J.; Romeo, T.; Parsek, M.R. Pseudomonas aeruginosa biofilm matrix polysaccharide Psl is regulated transcriptionally by RpoS and post-transcriptionally by RsmA. Mol. Microbiol. 2010, 78, 158-172
116. Hickman, J.W.; Tifrea, D.F.; Harwood, C.S. A chemosensory system that regulates biofilm formation through modulation of cyclic diguanylate levels. Proc. Natl. Acad. Sci. USA 2005, 102, 14422-14427
117. Irie, Y.; Borlee, B.R.; O’Connor, J.R.; Hill, P.J.; Harwood, C.S.; Wozniak, D.J.; Parsek, M.R. Self-produced exopolysaccharide is a signal that stimulates biofilm formation in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 2012, 109, 20632-20636
118. Remminghorst, U.; Rehm, B.H.A. Alg44, a unique protein required for alginate biosynthesis in Pseudomonas aeruginosa. FEBS Lett. 2006, 580, 3883-3888
119. Amikam, D.; Galperin, M.Y. PilZ domain is part of the bacterial c-di-GMP binding protein. Bioinformatics 2006, 22, 3-6
120. Merighi, M.; Lee, V.T.; Hyodo, M.; Hayakawa, Y.; Lory, S. The second messenger bis-(3’-5’)-cyclic-GMP and its PilZ domain-containing receptor Alg44 are required for alginate biosynthesis in Pseudomonas aeruginosa. Mol. Microbiol. 2007, 65, 876-895
121. Oglesby, L.L.; Jain, S.; Ohman, D.E. Membrane topology and roles of Pseudomonas aeruginosa Alg8 and Alg44 in alginate polymerization. Microbiology 2008, 154, 1605-1615
122. Starkey, M.; Hickman, J.H.; Ma, L.; Zhang, N.; de Long, S.; Hinz, A.; Palacios, S.; Manoil, C.; Kirisits, M.J.; Starner, T.D.; et al. Pseudomonas aeruginosa Rugose small-colony variants have adaptations that likely promote persistence in the cystic fibrosis lung. J. Bacteriol. 2009, 191, 3492-3503
123. Malone, J.G.; Jaeger, T.; Spangler, C.; Ritz, D.; Spang, A.; Arrieumerlou, C.; Kaever, V.; Landmann, R.; Jenal, U. YfiBNR mediates cyclic di-GMP dependent small colony variant formation and persistence in Pseudomonas aeruginosa. PLoS Pathog. 2010, 6, e1000804
124. Hrabak, E.M.; Willis, D.K. The lemA gene required for pathogenicity of Pseudomonas syringae pv. syringae on bean is a member of a family of two-component regulators. J. Bacteriol. 1992, 174, 3011-3020
125. Kay, E.; Humair, B.; Dénervaud, V.; Riedel, K.; Spahr, S.; Eberl, L.; Valverde, C.; Haas, D. Two GacA-dependent small RNAs modulate the quorum-sensing response in Pseudomonas aeruginosa. J. Bacteriol. 2006, 188, 6026-6033
126. Lapouge, K.; Schubert, M.; Allain, F.H.T.; Haas, D. Gac/Rsm signal transduction pathway of γ-proteobacteria: From RNA recognition to regulation of social behaviour. Mol. Microbiol. 2008, 67, 241-253
127. Pessi, G.; Williams, F.; Hindle, Z.; Heurlier, K.; Holden, M.T.G.; Cámara, M.; Haas, D.; Williams, P. The global posttranscriptional regulator RsmA modulates production of virulence determinants and N-acylhomoserine lactones in Pseudomonas aeruginosa. J. Bacteriol. 2001, 183, 6676-6683
128. Reimmann, C.; Beyeler, M.; Latifi, A.; Winteler, H.; Foglino, M.; Lazdunski, A.; Haas, D. The global activator GacA of Pseudomonas aeruginosa PAO positively controls the production of the autoinducer N-butyryl-homoserine lactone and the formation of the virulence factors pyocyanin, cyanide, and lipase. Mol. Microbiol. 1997, 24, 309-319
129. Marden, J.N.; Diaz, M.R.; Walton, W.G.; Gode, C.J.; Betts, L.; Urbanowski, M.L.; Redinbo, M.R.; Yahr, T.L.; Wolfgang, M.C. An unusual CsrA family member operates in series with RsmA to amplify posttranscriptional responses in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 2013, 110, 15055-15060
130. Morris, E.R.; Hall, G.; Li, C.; Heeb, S.; Kulkarni, R.V.; Lovelock, L.; Silistre, H.; Messina, M.; Cámara, M.; Emsley, J.; et al. Structural rearrangement in an RsmA/CsrA Ortholog of Pseudomonas aeruginosa creates a dimeric RNA-binding protein, RsmN. Structure 2013, 21, 1659-1671
131. Ventre, I.; Goodman, A.L.; Vallet-Gely, I.; Vasseur, P.; Soscia, C.; Molin, S.; Bleves, S.; Lazdunski, A.; Lory, S.; Filloux, A. Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes. Proc. Natl. Acad. Sci. USA 2006, 103, 171-176
132. Goodman, A.L.; Merighi, M.; Hyodo, M.; Ventre, I.; Filloux, A.; Lory, S. Direct interaction between sensor kinase proteins mediates acute and chronic disease phenotypes in a bacterial pathogen. Genes Dev. 2009, 23, 249-259
133. Chambonnier, G.; Roux, L.; Redelberger, D.; Fadel, F.; Filloux, A.; Sivaneson, M.; de Bentzmann, S.; Bordi, C. The hybrid histidine kinase LadS forms a multicomponent signal transduction system with the GacS/GacA two-component system in Pseudomonas aeruginosa. PLoS Genet. 2016, 12, e1006032
134. Broder, U.N.; Jaeger, T.; Jenal, U. LadS is a calcium-responsive kinase that induces acute-to-chronic virulence switch in Pseudomonas aeruginosa. Nat. Microbiol. 2016, 2, 16184
135. Miller, C.L.; Romero, M.; Rajasekhar Karna, S.L.; Chen, T.; Heeb, S.; Leung, K.P. RsmW, Pseudomonas aeruginosa small non-coding RsmA-binding RNA upregulated in biofilm versus planktonic growth conditions. BMC Microbiol. 2016, 16, 155
136. Brencic, A.; Lory, S. Determination of the regulon and identification of novel mRNA targets of Pseudomonas aeruginosaRsmA. Mol. Microbiol. 2009, 72, 612-632
137. Potvin, E.; Lehoux, D.E.; Kukavica-Ibrulj, I.; Richard, K.L.; Sanschagrin, F.; Lau, G.W.; Levesque, R.C. In vivo functional genomics of Pseudomonas aeruginosa for high-throughput screening of new virulence factors and antibacterial targets. Environ. Microbiol. 2003, 5, 1294-1308
138. Mougous, J.D.; Cuff, M.E.; Raunser, S.; Shen, A.; Zhou, M.; Gifford, C.A.; Goodman, A.L.; Joachimiak, G.; Ordonez, C.L.; Lory, S.; et al. A Virulence lous of Pseudomonas aeruginosa encodes a protein secretion apparatus. Science 2006, 312, 1526-1530
139. Coggan, K.A.; Wolfgang, M.C. Global regulatory pathways and cross-talk control Pseudomonas aeruginosa environmental lifestyle and virulence phenotype. Curr. Issues Mol. Biol. 2012, 14, 47-70
140. Mikkelsen, H.; McMullan, R.; Filloux, A. The Pseudomonas aeruginosa reference strain PA14 displays increased virulence due to a mutation in ladS. PLoS ONE 2011, 6, e29113
141. Jimenez, P.N.; Koch, G.; Thompson, J.A.; Xavier, K.B.; Cool, R.H.; Quax, W.J. The multiple signaling systems regulating virulence in Pseudomonas aeruginosa. Microbiol. Mol. Biol. Rev. 2012, 76, 46-65
142. Frangipani, E.; Visaggio, D.; Heeb, S.; Kaever, V.; Cámara, M.; Visca, P.; Imperi, F. The Gac/Rsm and cyclic-di-GMP signalling networks coordinately regulate iron uptake in Pseudomonas aeruginosa. Environ. Microbiol. 2014, 16, 676-688
143. Moscoso, J.A.; Mikkelsen, H.; Heeb, S.; Williams, P.; Filloux, A. The Pseudomonas aeruginosa sensor RetS switches Type III and Type VI secretion via c-di-GMP signalling. Environ. Microbiol. 2011, 13, 3128-3138
144. Moscoso, J.A.; Jaeger, T.; Valentini, M.; Hui, K.; Jenal, U.; Filloux, A. The diguanylate cyclase SadC is a central player in Gac/Rsm-mediated biofilm formation in Pseudomonas aeruginosa. J. Bacteriol. 2014, 196, 4081-4088
145. Yang, L.; Rybtke, M.T.; Jakobsen, T.H.; Hentzer, M.; Bjarnsholt, T.; Givskov, M.; Tolker-Nielsen, T. Computer-aided identification of recognized drugs as Pseudomonas aeruginosa quorum-sensing inhibitors. Antimicrob. Agents Chemother.2009, 53, 2432-2443
146. Tan, S.Y.-Y.; Liu, Y.; Chua, S.L.; Vejborg, R.M.; Jakobsen, T.H.; Chew, S.C.; Li, Y.; Nielsen, T.E.; Tolker-Nielsen, T.; Yang, L.; et al. Comparative systems biology analysis to study the mode of action of the isothiocyanate compound iberin on Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2014, 58, 6648-6659
147. Rybtke, M.T.; Borlee, B.R.; Murakami, K.; Irie, Y.; Hentzer, M.; Nielsen, T.E.; Givskov, M.; Parsek, M.R.; Tolker-Nielsen, T. Fluorescence-based reporter for gauging cyclic Di-GMP levels in Pseudomonas aeruginosa. Appl. Environ. Microbiol.2012, 78, 5060-5069
148. Rumbaugh, K.P.; Griswold, J.A.; Iglewski, B.H.; Hamood, A.N. Contribution of quorum sensing to the virulence of Pseudomonas aeruginosa in burn wound infections. Infect. Immun. 1999, 67, 5854-5862
149. Smith, R.S.; Harris, S.G.; Phipps, R.; Iglewski, B. The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. J. Bacteriol. 2002, 184, 1132-1139
150. Pearson, J.P.; Feldman, M.; Iglewski, B.H.; Prince, A. Pseudomonas aeruginosa cell-to-cell signaling is required for virulence in a model of acute pulmonary infection. Infect. Immun. 2000, 68, 4331-4334
151. Wu, H.; Song, Z.; Givskov, M.; Doring, G.; Worlitzsch, D.; Mathee, K.; Rygaard, J.; Høiby, N. Pseudomonas aeruginosamutations in lasI and rhlI quorum sensing systems result in milder chronic lung infection. Microbiology 2016, 2318, 34-1105
152. Christensen, L.D.; Moser, C.; Jensen, P.; Rasmussen, T.B.; Christophersen, L.; Kjelleberg, S.; Kumar, N.; Høiby, N.; Givskov, M.; Bjarnsholt, T. Impact of Pseudomonas aeruginosa quorum sensing of biofilm persistence in an in vivo intraperitoneal foreign-body infection model. Microbiology 2007, 153, 2312-2320
153. Xiao, G.; Déziel, E.; He, J.; Lépine, F.; Lesic, B.; Castonguay, M.H.; Milot, S.; Tampakaki, A.P.; Stachel, S.E.; Rahme, L.G. MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands. Mol. Microbiol. 2006, 62, 1689-1699
154. Givskov, M.; de Nys, R.; Manefield, M.; Gram, L.; Maximilien, R.; Eberl, L.; Molin, S.Ø.; Steinberg, P.D.; Kjelleberg, S. Eukaryotic interference with homoserine lactone-mediated prokaryotic signalling. J. Bacteriol. 1996, 178, 6618-6622
155. Rasmussen, T.B.; Skindersoe, M.E.; Bjarnsholt, T.; Phipps, R.K.; Christensen, K.B.; Jensen, P.O.; Andersen, J.B.; Koch, B.; Larsen, T.O.; Hentzer, M.; et al. Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology 2005, 151, 1325-1340
156. LaLonde, R.T.; Bu, L.; Henwood, A.; Fiumano, J.; Zhang, L. Bromine-, chlorine-, and mixed halogen-substituted 4-methyl-2(5H)-furanones: Synthesis and mutagenic effects of halogen and hydroxyl group replacements. Chem. Res. Toxicol. 1997, 10, 1427-1436
157. Janecki, T.; Błaszczyk, E.; Studzian, K.; Różalski, M.; Krajewska, U.; Janecka, A. New stereocontrolled synthesis and biological evaluation of 5-(1’-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones as Potential Cytotoxic Agents. J. Med. Chem. 2002, 45, 1142-1145
158. Kim, Y.; Nam, N.-H.; You, Y.-J.; Ahn, B.-Z. Synthesis and cytotoxicity of 3,4-diaryl-2(5H)-furanones. Bioorg. Med. Chem. Lett. 2002, 12, 719-722
159. Read, R.; Kumar, N. Production of Furanones. U.S. Patent 20070032666 A1, 8 February 2007
160. Galloway, W.R.J.D.; Hodgkinson, J.T.; Bowden, S.; Welch, M.; Spring, D.R. Applications of small molecule activators and inhibitors of quorum sensing in Gram-negative bacteria. Trends Microbiol. 2017, 20, 449-458
161. Passador, L.; Tucker, K.D.; Guertin, K.R.; Journet, M.P.; Kende, A.S.; Iglewski, B.H. Functional analysis of the Pseudomonas aeruginosa autoinducer PAI. J. Bacteriol. 1996, 178, 5995-6000
162. Ishida, T.; Ikeda, T.; Takiguchi, N.; Kuroda, A.; Ohtake, H.; Kato, J. Inhibition of quorum sensing in Pseudomonas aeruginosa by N-acyl cyclopentylamides. Appl. Environ. Microbiol. 2007, 73, 3183-3188
163. Smith, K.M.; Bu, Y.; Suga, H. Induction and inhibition of Pseudomonas aeruginosa quorum sensing by synthetic autoinducer analogs. Chem. Biol. 2003, 10, 81-89
164. Smith, K.M.; Bu, Y.; Suga, H. Library screening for synthetic agonists and antagonists of a Pseudomonas aeruginosaautoinducer. Chem. Biol. 2003, 10, 563-571
165. Mattmann, M.E.; Blackwell, H.E. Small molecules that modulate quorum sensing and control virulence in Pseudomonas aeruginosa. J. Org. Chem. 2010, 75, 6737-6746
166. Bottomley, M.J.; Muraglia, E.; Bazzo, R.; Carfì, A. Molecular insights into quorum sensing in the human pathogen Pseudomonas aeruginosa from the structure of the virulence regulator LasR bound to Its autoinducer. J. Biol. Chem. 2007, 282, 13592-13600
167. Zou, Y.; Nair, S.K. Molecular basis for the recognition of structurally distinct autoinducer Mimics by the Pseudomonas aeruginosa LasR quorum-sensing signaling receptor. Chem. Biol. 2009, 16, 961-970
168. Müh, U.; Schuster, M.; Heim, R.; Singh, A.; Olson, E.R.; Greenberg, E.P. Novel Pseudomonas aeruginosa quorum-sensing inhibitors identified in an ultra-high-throughput screen. Antimicrob. Agents Chemother. 2006, 50, 3674-3679
169. Rasmussen, T.B.; Bjarnsholt, T.; Skindersoe, M.E.; Hentzer, M.; Kristoffersen, P.; Köte, M.; Nielsen, J.; Eberl, L.; Givskov, M. Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J. Bacteriol. 2005, 187, 1799-1814
170. Bjarnsholt, T.; Jensen, P.Ø.; Rasmussen, T.B.; Christophersen, L.; Calum, H.; Hentzer, M.; Hougen, H.P.; Rygaard, J.; Moser, C.; Eberl, L.; et al. Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology 2005, 151, 3873-3880
171. Persson, T.; Hansen, T.H.; Rasmussen, T.B.; Skinderso, M.E.; Givskov, M.; Nielsen, J. Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic. Org. Biomol. Chem. 2005, 3, 253-262
172. Pratt, D.A. Garlic and other alliums. The lore and the science. By eric block. Angew. Chem. Int. Ed. 2010, 49, 7162
173. Block, E.; Ahmad, S.; Jain, M.K.; Crecely, R.W.; Apitz-Castro, R.; Cruz, M.R. The chemistry of alkyl thiosulfate esters. 8. (E,Z)-Ajoene: A potent antithrombotic agent from garlic. J. Am. Chem. Soc. 1984, 106, 8295-8296
174. Jakobsen, T.H.; Bragason, S.K.; Phipps, R.K.; Christensen, L.D.; van Gennip, M.; Alhede, M.; Skindersoe, M.; Larsen, T.O.; Høiby, N.; Bjarnsholt, T.; et al. Food as a source for quorum sensing inhibitors: Iberin from horseradish revealed as a quorum sensing inhibitor of Pseudomonas aeruginosa. Appl. Environ. Microbiol. 2012, 78, 2410-2421
175. Ganin, H.; Rayo, J.; Amara, N.; Levy, N.; Krief, P.; Meijler, M.M. Sulforaphane and erucin, natural isothiocyanates from broccoli, inhibit bacterial quorum sensing. Med. Chem. Commun. 2013, 4, 175-179
176. Amara, N.; Mashiach, R.; Amar, D.; Krief, P.; Spieser, S.A.H.; Bottomley, M.J.; Aharoni, A.; Meijler, M.M. Covalent inhibition of bacterial quorum sensing. J. Am. Chem. Soc. 2009, 131, 10610-10619
177. Fong, J.; Yuan, M.; Jakobsen, T.H.; Mortensen, K.T.; Delos Santos, M.M.S.; Chua, S.L.; Yang, L.; Tan, C.H.; Nielsen, T.E.; Givskov, M. Disulfide bond-containing ajoene Analogues As Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa. J. Med. Chem. 2017, 60, 215-227
178. Jakobsen, T.H.; van Gennip, M.; Phipps, R.K.; Shanmugham, M.S.; Christensen, L.D.; Alhede, M.; Skindersoe, M.E.; Rasmussen, T.B.; Friedrich, K.; Uthe, F.; et al. Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing. Antimicrob. Agents Chemother. 2012, 56, 2314-2325
179. Manefield, M.; Rasmussen, T.B.; Henzter, M.; Andersen, J.B.; Steinberg, P.; Kjelleberg, S.; Givskov, M. Halogenated furanones inhibit quorum sensing through accelerated LuxR turnover. Microbiology 2002, 148, 1119-1127
180. Jakobsen, T.H.; Warming, A.N.; Vejborg, R.M.; Moscoso, J.A.; Stegger, M.; Lorenzen, F.; Rybtke, M.; Andersen, J.B.; Petersen, R.; Andersen, P.S.; et al. A broad range quorum sensing inhibitor working through sRNA inhibition. Sci. Rep.2017, in press
181. Pérez-Martínez, I.; Haas, D. Azithromycin inhibits expression of the GacA-dependent small RNAs RsmY and RsmZ in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2011, 55, 3399-3405
182. Skindersoe, M.E.; Alhede, M.; Phipps, R.; Yang, L.; Jensen, P.O.; Rasmussen, T.B.; Bjarnsholt, T.; Tolker-Nielsen, T.; Høiby, N.; Givskov, M. Effects of antibiotics on quorum sensing in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2008, 52, 3648-3663
183. Sambanthamoorthy, K.; Sloup, R.E.; Parashar, V.; Smith, J.M.; Kim, E.E.; Semmelhack, M.F.; Neiditch, M.B.; Waters, C.M. Identification of small molecules that antagonize diguanylate cyclase enzymes to inhibit biofilm formation. Antimicrob. Agents Chemother. 2012, 56, 5202-5211
184. Sambanthamoorthy, K.; Luo, C.; Pattabiraman, N.; Feng, X.; Koestler, B.; Waters, C.M.; Palys, T.J. Identification of small molecules inhibiting diguanylate cyclases to control bacterial biofilm development. Biofouling 2014, 30, 17-28
185. Lieberman, O.J.; Orr, M.W.; Wang, Y.; Lee, V.T. High-throughput screening using the differential radial capillary action of ligand assay identifies ebselen as an inhibitor of diguanylate cyclases. ACS Chem. Biol. 2014, 9, 183-192
186. Groizeleau, J.; Rybtke, M.; Andersen, J.B.; Berthelsen, J.; Liu, Y.; Yang, L.; Nielsen, T.E.; Kaever, V.; Givskov, M.; Tolker-Nielsen, T. The anti-cancerous drug doxorubicin decreases the c-di-GMP content in Pseudomonas aeruginosa but promotes biofilm formation. Microbiology 2016, 162, 1797-1807
187. Zhou, J.; Watt, S.; Wang, J.; Nakayama, S.; Sayre, D.A.; Lam, Y.F.; Lee, V.T.; Sintim, H.O. Potent suppression of c-di-GMP synthesis via I-site allosteric inhibition of diguanylate cyclases with 2’-F-c-di-GMP. Bioorg. Med. Chem. 2013, 21, 4396-4404
188. Zheng, Y.; Tsuji, G.; Opoku-Temeng, C.; Sintim, H.O. Inhibition of P. aeruginosa c-di-GMP phosphodiesterase RocR and swarming motility by a benzoisothiazolinone derivative. Chem. Sci. 2016, 7, 6238-6244
189. Christensen, L.D.; van Gennip, M.; Jakobsen, T.H.; Alhede, M.; Hougen, H.P.; Høiby, N.; Bjarnsholt, T.; Givskov, M. Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model. J. Antimicrob. Chemother. 2012, 67, 1198-1206
190. Brackman, G.; Cos, P.; Maes, L.; Nelis, H.J.; Coenye, T. Quorum sensing inhibitors increase the susceptibility of bacterial biofilms to antibiotics in vitro and in vivo. Antimicrob. Agents Chemother. 2011, 55, 2655-2661
191. Høiby, N. Recent advances in the treatment of Pseudomonas aeruginosa infections in cystic fibrosis. BMC Med. 2011, 9, 32